With the advent of disease-modifying therapies, the life span of patients with multiple sclerosis has increased dramatically.
CM is a 65-year-old female presenting to the neurology clinic with a past medical history of relapsing/remitting multiple sclerosis (MS). Her initial symptoms at diagnosis were sensory loss in her left leg and optic neuritis.
After diagnosis, it was decided to start disease-modifying therapy (DMT) on interferon beta-1a. CM remained on this therapy for 13 years. She suffered from multiple relapses, including a relapse that resulted in hospitalization and steroid treatments.
The MRI results showed multiple enhancing lesions. The provider switched therapy to fingolimod. After 7 years of fingolimod therapy, CM suffered another severe relapse, resulting in hospitalization requiring treatment with SoluMedrol.
After multiple severe relapses and complications surrounding a car accident, CM is no longer ambulatory. She is in an assisted living facility, has an indwelling catheter, and has multiple reoccurring infections. Her EDSS score is 8.
In 2021, the provider discontinued all DMTs due to the risk of infection outweighing the benefits of prevention of relapses and disease progression due to the high EDSS score.
Today, a year later, she is presenting to the neurology clinic with the question of whether to restart a DMT to prevent relapses.What is your recommendation to the provider?
Finger to nose coordination: normal
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MS is an autoimmune disease characterized by inflammation, demyelination, and axonal degeneration. MS primarily affects women with a ratio of 3:1 compared to men with an initial diagnosis age ranging from 20 to 40 years.1
According to the International Advisory Committee on Clinical Trials of MS, there are 4 main disease courses—clinically isolated syndrome (CIS), relapsing/remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS). RRMS is the most common disease course, with approximately 85% of patients initially diagnosed in this stage. Patients with RRMS form cycles between relapses followed by periods of complete or partial recovery.1
With the advent of DMTs, the life span of patients with MS has increased dramatically. Approximately 25% of patients with MS are adults over 65 years of age.2
Health care providers face unique challenges in treating an elderly patient with MS. Elderly patients suffer from age-related and MS-related comorbidities with the disease course shifting from an inflammatory to a neurodegenerative phenotype. Among older adults, limited data exist for prescribing patterns of DMTs.
A retrospective longitudinal cohort study examined the prescribing patterns of DMTs in older adults with MS.3 The study cohort consisted of 12,922 patients with MS aged 60 years and older, with 2455 patients receiving DMT therapy.
The most commonly prescribed DMTs were injectables (10.46%), orals (6.06%), and infusions (2.40%). The authors concluded nearly 1 in 5 older adults with MS were prescribed DMTs, with injectables being the most common form.
CMs condition has deteriorated over time and her EDSS score is currently 8. Clinical trials routinely exclude patients of CM’s age and with her degree of disability.
Hence, health care providers face a lack of knowledge of the safety and efficacy of DMTs in the elderly population. Often, providers will discontinue treatment because of increased risk and decreased benefit to the patient.
CM and her nurse advocate favor preserving and maintaining her quality of life. CM is still very functional cognitively and has fine upper extremity mobility.
Because future relapses could affect CM’s quality of life—after discussions with the patient, and the patient advocate—the provider decided to initiate CM on diroximel fumarate. Although the platform therapies of glatiramer acetate and interferon-beta1a are safest in the elderly population, CM was not interested in any injectable forms.
DMTs can cause varying degrees of lymphopenia, which is classified as grade 1 (mild lymphopenia) ALC < lower limit of normal to 800/mm3, grade 2 (moderate lymphopenia) ALC < 800–500/mm3, grade 3 (severe lymphopenia) ALC < 500–200/mm3 and grade 4 < 200/mm3.
In the general population, lymphopenia is associated with increased risk of hospitalization and increased risk of infection-related death.4 In patients with MS, this increased risk of infection is likely to be elevated due to comorbidities and the immunocompromised state.
Diroximel fumarate is used to treat both RRMS and active SPMS.5 It has an unknown mechanism of action but does activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway reducing cellular oxidative stress.
CM is at a high risk of infection due to her baseline wheelchair status, prior infections, and indwelling catheter. In clinical trials with dimethyl fumarate (has the same active metabolite as diroximel fumarate), mean lymphocyte counts decreased by 30% during the first year of treatment, and then remained stable thereafter.5
CM requires close monitoring—she will need CBC including lymphocyte count at baseline, and every 6 months thereafter, and MRI at baseline and then for routine monitoring.5 If CM exhibits any disease activity (either clinical or on radiograph) after initiating diroximel fumarate, the provider should stop the medication due to the altered risk versus benefit scenario. Diroximel fumarate can cause liver toxicity—serum aminotransferase, alkaline phosphates, and total bilirubin levels must be checked before initiation and during treatment as clinically indicated.
The starting dose of diroximel fumarate is 231 mg twice a day orally.5 The dose is increased to 462 mg twice a day after 7 days.
The pharmacist should counsel CM to take the medication with a meal or snack containing no more than 700 calories and 30 grams of fat to reduce flushing. Although diroximel fumarate causes less GI distress compared to dimethyl fumarate, CM should be counseled on abdominal pain, diarrhea, and nausea.5
PML is an opportunistic infection caused by the JC virus in immunocompromised patients. CM has tested negative for the JCV virus, but she should be counseled on the signs and symptoms of PML which include progressive weakness on one side of the body or clumsiness of limbs, visual changes, changes in memory, and orientation leading to confusion and personality changes. Patients may also develop herpes zoster or other opportunistic infections while on therapy.
The safety and efficacy of live or live-attenuated vaccines with diroximel fumarate has not been assessed.5 According to the National MS Society guidelines, no adjustments are required with diroximel fumarate and COVID-19 vaccine administration.6
About the Authors
Justin Bivona is a specialty clinical pharmacist working in multiple sclerosis and rare diseases at the Outpatient Pharmacy Services (OPS).
Bisni Narayanan, PharmD, MS is the supervisor for operations at OPS. OPS is a specialty pharmacy integrated within the Yale New Health System.